The invention relates to an improved process for the preparation of the antidepressant fluoxetine or N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine of formula (I), ##STR1## and pharmaceutically acceptable salts thereof, preferably the hydrochloride.
Fluoxetine, the pharmacological effect of which is based on its in vivo inhibiting effect on serotonin (5HT) uptake and which consequently is used as an efficient antidepressant, is a well-known compound.
Thus, the preparation of fluoxetine is earlier described, among other places, in U.S. Pat. No. 4,314,081 and in GB Patent Application No. 2,060,618, and the preparation of fluoxetine type compounds is presented in U.S. Pat. No. 4,296,126.
The object of this invention is to provide a new, more economical, safer in occupational safety and environmental protection points of view and improved process with higher yields for the production of fluoxetine.
Characteristic of the process of the present invention is, that 1-phenyl-3-(N-methylamino)propan-1-ol of formula (III) ##STR2## is selectively etherified with 1-chloro-4-trifluoromethylbenzene of formula (IV) ##STR3## in the presence of potassium t-butoxide, resulting in fluoxetine base of formula (I) of a high purity and in good yield. The resulting base may be transformed in a known manner into a pharmaceutically acceptable salt thereof.
1-Phenyl-3-(N-methylamino)propan-1-ol of formula (III) is preferably obtained by catalytical hydrogenation and debenzylation of 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base of formula (II) ##STR4## with the aid of a hydrogenation catalyst.
In the process for the preparation of fluoxetine, as in U.S. Pat. No. 4,314,081, .beta.-dimethylaminopropiophenone hydrochloride is used as a starting material which, after the liberation of the base, is hydrogenated with diborane, B.sub.2 H.sub.4. The N,N-dimethyl-3-hydroxy-3-phenylpropylamine produced in the reaction is allowed to react with thionyl chloride in chloroform containing hydrochloric acid yielding N,N-dimethyl-3-phenyl-3-chloropropylamine. This compound is allowed to react under alkaline conditions with p-trifluoro-methylphenol by heating the mixture under reflux for 5 days and nights, after which N,N-dimethyl-3-p-trifluoromethylphenoxy-3-phenylpropylamine is produced. This compound is N-demethylated with the aid of cyanogen bromide, yielding N-methyl-N-cyano-3-(p-trifuoromethylphenoxy)-phenylpropylamine. The N-cyano group is removed from this compound by heating for 20 hours at 130.degree. C. under reflux in a mixture of potassium hydroxide and ethylene glycol. The reaction mixture is extracted with ether and the ether phase is evaporated to dryness. The residue could further be transformed in a known manner into a pharmaceutically acceptable salt of fluoxetine.
Several processes are described in GB 2,060,618, and one of them is concerned with the preparation of fluoxetine. In said process N-methyl-3-hydroxy-3-phenylpropylamine is used as a starting material, which is allowed to react with 1-fluoro-4-trifluoromethylbenzene in the presence of sodium hydride using dimethylsulfoxide as a solvent. The mixture is heated to 80.degree. C., whereafter it is allowed to cool to room temperature. The oily residue is poured on a mixture of ice and water, which is extracted with ether. The ether phase is dried and ether is distilled off under vacuum. The residue is dissolved in ether and ether-hydrochloric acid (g) is added whereby the hydrochloride salt of fluoxetine is precipitated. The precipitate is filtered, washed with ether and dried under vacuum.
The etherification of 1-phenyl-3-(N,N-dialkylamino)-propan-1-ol type compounds with 1-halogen substituted trifluoromethylnitrobenzene is described in U.S. Pat. No. 4,296,126. This etherification reaction proceeds when an activating nitro group is attached to the phenyl ring. The reaction is carried out in the presence of sodium hydride and in a compatible solvent.
When compared with the methods mentioned before, the process according to the present invention for the preparation of fluoxetine hydrochloride is performed technically as well as economically in a more advantageous way.
In the preferred over-all method for producing of fluoxetine 1-phenyl-3-(N-methylamino)-propan-1-ol (III) is selectively etherified in the presence of potassium t-butoxide with halogen substituted p-trifluoromethylbenzene wherein the halogen may be F, Cl or Br, and the preferred reagent is 1-chloro-4-trifluoromethylbenzene. The process is carried out in an organic aprotic solvent such as N-methylpyrrolidone or dimethylsulfoxide. When using other aprotic solvents there occurs undesired side reactions, the yields are low and there appear impurities in the product. N-methylpyrrolidone is preferably used because the use of dimethylsulfoxide may produce sulfur containing waste, which is difficult to dispose of. The reaction proceeds via an alcoholate intermediate with potassium t-butoxide, which thus is not solely acting as a base. The temperature for the etherification step is generally about 20.degree. to 200.degree. C., preferably 80.degree. C.
The said starting material 2-benzoyl-1-(N-benzyl-N-methyl)ethylamine base (II) is a known compound and it may be produced using methods which are in themselves known. Said base (II) is simultaneously catalytically hydrogenated and debenzylated with the aid of a hydrogenation catalyst such as Pd/C, Pt/C or Pd-Pt/C. The reaction is performed under hydrogen pressure of approximately 1-20 bar, preferably 5 bar, and at a temperature of approximately 20.degree.-100.degree. C., preferably 50.degree. C., using inert solvents such as alcohols, preferably ethanol, isopropanol, 2-butanol, n-butanol, methanol and amyl alcohol, esters, preferably ethyl acetate, and butyl acetate, toluene and tetrahydrofurane. The simultaneous catalytic hydrogenation and debenzylation yields 1-phenyl-3-(N-methylamino)propan-1-ol (III).
Performed in this way, a N-methyl-3-(p-trifluoromethyl-phenoxy)-3-phenylpropylamine base in high yield is obtained, which may be transformed in a known manner in an almost theoretical yield into the corresponding hydrochloride salt (I).
The process of the present invention has several considerable advantages over the processes described earlier.
Thus, according to the process as described in U.S. Pat. No. 4,314,081, N,N-dimethylaminopropiophenone is used as a starting material, which is then after several process steps converted to N,N-dimethyl-3-p-trifluoromethylphenoxy-3-phenylpropylamine intermediate. A complicated N-demethylation step using cyanogen bromide, which is highly poisonous, tends to explode easily (Merck Index 11th ed. p. 420) and it may cause toxic impurities in the product, is performed on this intermediate, which is then further processed t yield fluoxetine.
According to the process of the invention, instead of a methyl group a benzyl group is used as a protecting group which is required in the reaction to produce compound II and thus the simultaneous debenzylation and catalytic hydrogenation of the benzylated .beta.-amino-ketone is performed and the difficult and disadvantageous demethylation can be avoided, which is a significant improvement particularly from occupational safety and environmental protection points of view. According to our knowledge this kind of simultaneous debenzylation and catalytic hydrogenation of this type of .beta.-aminoketones has not been described in literature. Also the number of reaction steps is reduced from 6 to 3 which results in a marked increase in the total yield of the process.
The process of the present invention also has another considerable advantage over the process described in U.S. Pat. No. 4,314,081. According to the preferred embodiment of the process of the present invention, 1-phenyl-3-(N-methylamino)-propan-1-ol is allowed to react with p-chlorobenzotrifluoride. It was surprising that the etherification reaction proceeds readily with good yield using p-chlorobenzotrifluoride, because it is well known that the respective p-fluoro-compounds are much more reactive than other halides and usually activating groups such as nitro etc. are required.
According to U.S. Pat. No. 4,314,081 p-trifluoro-methylphenol was heated together with N,N-dimethyl-3-phenyl-3-chloropropylamine for about 5 days in order to obtain at least some N,N-dimethyl-3-p-trifluoro-methylphenoxy-3-phenylpropylamine. Moreover, the above mentioned complicated N-demethylation has to be performed on this intermediate. In the investigations which the present inventors have performed on the above mentioned process, they obtained at most a 20 yield due to the fact that the hydroxy group of p-trifluoromethylphenol reacts very poorly with the chloro substituent of N,N-dimethyl-3-phenyl-3-chloropropylamine. The process according to the invention is therefore superior from technical environmental, occupational safety and economical points of view compared to the process as described in U.S. Pat. No. 4,314,081.
In the process according to GB 2,060,618, sodium hydride is used as a reagent. Sodium hydride is very predisposed to explode, especially when it comes in contact with humidity. The reaction has thus to be performed under completely dry conditions, which is very difficult to achieve on an industrial scale.
These problems can be avoided when using potassium t-butoxide as it is described in the process of the present invention. It is significant to note that sodium hydride has been used as the reagent for production of fluoxetine and its homologs in most of the prior known processes wherein compound (III) is used as the starting material.
According to the process of the present invention, sodium hydride can be substituted with potassium-t-butoxide, the use of which is completely safe on an industrial scale.
The yield of fluoxetine hydrochloride is only 63.4 % according to the process in the examples of GB 2,060,618, when again a yield over 85 % is achieved according to the process of the present invention. Moreover, large quantities of the sodium hydride are needed for etherification, which is very hazardous for occupational safety reasons.
When comparing the process of the present invention with the process described in GB 2,060,618, it could be observed, that when etherifying 1-phenyl-3-(N-methylamino)-propan-1-ol according to the process of the present invention using p-chloro-benzotrifluoride the reaction proceeds surprisingly well and the chloro reagent is significantly cheaper than p-fluorobenzotrifluoride used in GB 2,060 618.
The process of the present invention has thus considerable technical, enonomical as well as occupational safety advantages when compared to the process as described in GB 2,060,618.
When compared with the process described in U.S. Pat. No. 4,296,126 the present invention has several advantages. The etherification reaction presented in the U.S. patent proceeds when the activating nitro group is attached to the phenyl ring, and in the reaction of the present invention no activating groups are needed. Sodium hydride, which has several disadvantages as mentioned earlier, is used as a base in the process described in the U.S. patent. In the present invention potassium t-butoxide is used and the reaction proceeds via an alcoholate intermediate and the liberation of hydrogen can thus be avoided.